UBR-1 ubiquitin ligase regulates the balance between GABAergic and glutamatergic signaling.

Excitation/inhibition (E/I) balance is carefully maintained by the nervous system. The neurotransmitter GABA has been reported to be co-released with its sole precursor, the neurotransmitter glutamate. The genetic and circuitry mechanisms to establish the balance between GABAergic and glutamatergic signaling have not been fully elucidated. Caenorhabditis elegans DVB is an excitatory GABAergic motoneuron that drives the expulsion step in the defecation motor program. We show here that in addition to UNC-47, the vesicular GABA transporter, DVB also expresses EAT-4, a vesicular glutamate transporter. UBR-1, a conserved ubiquitin ligase, regulates DVB activity by suppressing a bidirectional inhibitory glutamate signaling. Loss of UBR-1 impairs DVB Ca2+ activity and expulsion frequency. These impairments are fully compensated by the knockdown of EAT-4 in DVB. Further, glutamate-gated chloride channels GLC-3 and GLC-2/4 receive DVB's glutamate signals to inhibit DVB and enteric muscle activity, respectively. These results implicate an intrinsic cellular mechanism that promotes the inherent asymmetric neural activity. We propose that elevated glutamate in ubr-1 mutants, being the cause of the E/I shift, potentially contributes to Johanson Blizzard syndrome.

Alterations in descending brain-spinal pathways regulating colorectal motility in a rat model of Parkinson's disease.

Patients with Parkinson's disease (PD) often have constipation. It is assumed that a disorder of the regulatory mechanism of colorectal motility by the central nervous system is involved in the constipation, but this remains unclear. The aim of this study was to investigate whether central neural pathways can modulate colorectal motility in a rat model of PD. PD model rats were generated by injection of 6-hydroxydopamine into a unilateral medial forebrain bundle and destruction of dopaminergic neurons in the substantia nigra. Colorectal motility was measured in vivo in anesthetized rats. Intraluminal administration of capsaicin, as a noxious stimulus, induced colorectal motility in sham-operated rats but not in PD rats. Intrathecally administered dopamine (DA) and serotonin (5-HT), which mediate the prokinetic effect of capsaicin, at the L6-S1 levels enhanced colorectal motility in PD rats similarly to that in sham-operated rats. In PD rats, capsaicin enhanced colorectal motility only when a GABAA receptor antagonist was preadministered into the lumbosacral spinal cord. Capsaicin-induced colorectal motility was abolished by intrathecal administration of a D2-like receptor antagonist but not by administration of 5-HT2 and 5-HT3 receptor antagonists. These findings demonstrate that the inhibitory GABAergic component becomes operative and the stimulatory serotonergic component is suppressed in PD rats. The alteration of the central regulatory mechanism of colorectal motility is thought to be related to the occurrence of constipation in PD patients. Our findings provide a new insight into the pathogenesis of defecation disorders observed in PD.NEW & NOTEWORTHY In a rat model of Parkinson's disease, the component of descending brain-spinal pathways that regulate colorectal motility through a mediation of the lumbosacral defecation center was altered from stimulatory serotonergic neurons to inhibitory GABAergic neurons. Our findings suggest that chronic constipation in Parkinson's disease patients may be associated with alterations in central regulatory mechanisms of colorectal motility. The plasticity in the descending pathway regulating colorectal motility may contribute to other disease-related defecation abnormalities.

Defecation symptoms in primary health care patients with irritable bowel syndrome.

BACKGROUND: The objectives of the present study were to (a) measure the prevalence of defecation symptoms in IBS, (b) investigate the relationship between stool consistency and defecation symptoms in IBS, and (c) investigate the association of defecation symptoms with health-related quality of life (HRQL) and self-reported stress in patients with IBS cared for in a primary health care setting. METHODS: Ten primary health care centres joined the study. 282 patients with IBS as well as 372 non-IBS controls filled in gastrointestinal symptom diaries prospectively for two weeks as well as the Perceived Stress Scale-14 (PSS14) and the EuroQol barometer to measure perceived stress and HRQL, respectively. RESULTS: Incomplete evacuation was present in 51% vs. 21% of the stools among the IBS patients and the non-IBS controls, respectively. The need to strain during defecation was existing in 41% vs. 33% of the stools for the IBS patients and the non-IBS controls, respectively. Urgency was experienced in 37% of the stools in the IBS patients compared with 18% of the stools in the non-IBS controls. Patients with IBS experienced in a significant higher degree of overlapping symptoms per stool (p < 0.001 to p = 0.007). The occurrence of all defecation symptoms in the same patient was related to decreased HRQL, and increased stress (p = 0.001 to p < 0.001). CONCLUSIONS: An overlap between IBS and symptoms from the anorectal region related to defecation was found in a primary health care population. Defecation symptoms are very common in primary care IBS-patients, it co-occurs with increased self-perceived stress, and decreased HRQL.

High-resolution anorectal manometry for diagnosing obstructed defecation syndrome associated with moderate rectocele compared to healthy individuals.

BACKGROUND: Few studies have investigated healthy female individuals (HFI) and those with obstructed defecation syndrome associated with moderate rectocele in women (MRW), identified using three-dimensional high-resolution anorectal manometry (3D HRAM) parameters that correlate with age stratification. OBJECTIVE: We aimed to explore the clinical diagnostic values of the MRW and HFI groups using 3D HRAM parameters related to age stratification. METHODS: A prospective non-randomized controlled trial involving 128 cases from the MRW (treatment group, 68 cases) and HFI (control group, 60 cases) groups was conducted using 3D HRAM parameters at Tianjin Union Medical Center between January 2017 and June 2022, and patients were divided into two subgroups based on their ages: the ≥50 and < 50 years subgroups. RESULTS: Multivariate binary logistic regression analysis showed that age (P = 0.024) and rectoanal inhibitory reflex (P = 0.001) were independent factors affecting the disease in the MRW group. Compared to the HFI group, the receiver operating characteristic (ROC) curve demonstrated that the 3D HRAM parameters exhibited a higher diagnostic value for age (Youden index = 0.31), urge to defecate (Youden index = 0.24), and rectoanal pressure differential (Youden index = 0.21) in the MRW group. CONCLUSIONS: Compared to the HFI group, the ROC curve of the 3D HRAM parameters suggests that age, urge to defecate, and rectoanal pressure differential in the MRW group have a significant diagnostic value. Because the Youden index is lower, 3D HRAM cannot be considered the gold standard method for diagnosing MRW.

Efficacy of lubiprostone for functional constipation treatment in adolescents and children: Randomized controlled trial.

OBJECTIVES: Adolescent and pediatric functional constipation (FC) is a common clinical problem. Currently, data on lubiprostone for the treatment of pediatric FC are scarce. This study investigated the efficacy and safety of lubiprostone in the treatment of pediatric FC. METHODS: In a single-blinded, randomized controlled study, we included 280 patients aged 8-18 years with FC. Patients were randomized either to a weight-based lubiprostone dose (n = 140) or conventional laxatives (n = 140), including lactulose, bisacodyl, or sodium picosulfate, for 12 weeks, followed by 4 weeks posttreatment follow-up. RESULTS: Improvement in constipation was achieved in 128 (91.4%) patients in the lubiprostone group, and in 48 (34.3%) patients of the conventional therapy group (p < 0.001) and was sustained after treatment discontinuation. One quarter of the lubiprostone group experienced the first spontaneous bowel motion within 48 h after dose initiation. A total of 75.7% of the lubiprostone group could achieve and sustain Bristol stool form of 3 or 4 during the last 4 weeks of therapy and through the 4 weeks of follow-up versus 50 (35.7%) patients in the conventional therapy group (p < 0.001). No life-threatening adverse drug reactions were encountered, and no treatment-related discontinuation. Mild self-limited colicky abdominal pain and headache were the most prevalent side effects in the lubiprostone group. CONCLUSIONS: Lubiprostone is an effective and well-tolerated pharmacotherapy for youthful age and pediatric age groups, which may alter the paradigm of pediatric FC treatment.

Digital Rectal Exams Are Infrequently Performed Prior to Anorectal Manometry.

BACKGROUND: Digital rectal examination should be performed prior to anorectal manometry; however, real-world data is lacking. AIMS: Characterize real world rates of digital rectal and their sensitivity for detecting dyssynergia compared to anorectal manometry and balloon expulsion test. METHODS: A retrospective single-center study was conducted to examine all patients who underwent anorectal manometry for chronic constipation between 2021 and 2022 at one tertiary center with motility expertise. Primary outcomes consisted of the rate of digital rectal exam prior to anorectal manometry; and secondary outcomes included the sensitivity of digital rectal exam for dyssynergic defecation. RESULTS: Only 42.3% of 142 patients had digital rectal examinations prior to anorectal manometry. Overall sensitivity for detecting dyssynergic defecation was 46.4%, but significantly higher for gastroenterology providers (p = .004), and highest for gastroenterology attendings (82.6%). CONCLUSIONS: Digital rectal examination is infrequently performed when indicated for chronic constipation. Sensitivity for detecting dyssynergic defecation may be impacted by discipline and level of training.

High Prevalence of Anorectal Dysfunction in Ambulatory Patients with Chronic Constipation, Regardless of Colon Transit Time.

BACKGROUND: Classification of chronic constipation (CC) into its three subtypes of slow transit constipation, defecation disorder and normal transit constipation, may improve its multifaceted management. We assessed the merits of the London classification in patients with CC, who were studied by both wireless motility capsule (WMC) and high-resolution anorectal manometry (HR-ARM), examining their relative utilities in decision-making.s PATIENTS AND METHODS: Retrospective, community-based study of prospectively collected data on patients with CC by Rome IV criteria, who underwent WMC and HR-ARM, Balloon Expulsion Test, and Rectal Sensory Testing. Clinical assessment was made by standard questionnaires. On WMC, standard criteria for colonic transit time (CTT) were used (normal CTT < 59 h). The hierarchical London classification was used for HR-ARM analyses. RESULTS: Of 1261 patients with CC, 166 (91 M; ages 22-86) received technically satisfactory WMC and HR-ARM, formed the analyzed study cohort, of whom 84 had normal CTT and 82 had prolonged CTT (> 59 h). Patients with slow CTT were significantly older and had longer duration and more severe disease. Using the London classification criteria for disorders of anorectal function, we noted a high prevalence of anorectal dysfunction, regardless of CTT. Except for lower rate of anal hypertonicity in patients with slow CTT, disorders of recto-anal coordination, and rectal sensation were seen at a comparable rate in patients with CC, regardless of CTT. CONCLUSION: There is a significant overlap of anorectal disorders in patients with slow CTT. There is questionable specificity and utility of WMC and HR-ARM in assessing patients with CC. More work is needed to demonstrate the value of these studies as surrogate markers of the disease and its response to multifaceted therapy.

Relationship of Age and Gender to Motility Test Results and Symptoms in Patients with Chronic Constipation.

BACKGROUND/AIMS: Patients with chronic constipation (CC) exhibit symptoms and functional abnormalities upon testing, but their relationship to age and gender is unclear. We assessed age- and gender-related differences in symptoms, colon transit time, and anorectal motility, sensation, and expulsion. PATIENTS AND METHODS: Retrospective, post hoc data analysis of patients with CC, who underwent Wireless Motility Capsule (WMC), High-Resolution Anorectal Manometry (HR-ARM), Balloon Expulsion Test (BET) and Rectal Sensory Testing (RST). Clinical assessment was made by questionnaires. Standard WMC criteria for colonic transit time (CTT) and the London classification was used for HR-ARM analyses, and regression plots between age, gender, CTT, HR-HRM, RST and BET were calculated. RESULTS: We studied 75 women and 91 men. Abdominal pain, infrequent defecation, incomplete evacuation, defecatory straining, and multiple motility and anorectal function abnormalities were common. Abdominal pain was least frequently, and straining was most frequently associated with a motility abnormality. For each symptom, the highest prevalence was associated with failed BET. There was a significant increase in CTT with age only in men (p = 0.0006). In men, for each year of age there was a CTT increase of 1.02 h. The prevalence of abdominal pain and incomplete evacuation for females was significantly higher than that for males (both P < 0.05). The prevalence of low anal squeeze pressure for females was significantly higher than that for males, and the prevalence of poor rectal sensation for males was significantly higher than that for females (both P < 0.05). A significant decrease in basal anal and squeeze pressures with age occurred in women (p < 0.0001); an increase in age of one year was associated with a decrease in anal base pressure of 1.2 mmHg. Abnormal CTT and HR-ARM tests were associated with increased symptom frequency, but not severity. CONCLUSIONS: There are significant age- and gender-related differences in symptoms, CTT, and HR-HRM parameters, rectal sensation, and expulsion, that may influence the multifaceted management of constipation.

Household environment associated with anaemia among children aged 6-59 months in Ethiopia: a multilevel analysis of Ethiopia demographic and health survey (2005-2016).

BACKGROUND: Anaemia continues to be a major public health challenge globally, including in Ethiopia. Previous studies have suggested that improved household environmental conditions may reduce anaemia prevalence; however, population-level evidence of this link is lacking in low-income countries. Therefore, this study aimed to examine the association between environmental factors and childhood anaemia in Ethiopia. METHODS: In this study, we conducted an analysis of the data from the Ethiopian Demographic and Health Survey (EDHS), a nationally representative population-based survey conducted in Ethiopia between 2005 and 2016. The study included a total of 21,918 children aged 6-59 months. Children were considered anemic if their hemoglobin (Hb) concentration was less than 11.0 g/dl. To examine the association between environmental factors and anemia, we used multilevel mixed-effect models. These models allowed us to control for various confounding factors including: child, maternal, household and community-level variables. The study findings have been reported as adjusted odds ratios (AORs) along with 95% confidence intervals (CIs) at a significance level of p < 0.05. RESULTS: The study found the overall prevalence of childhood anaemia to be 49.3% (95%CI: 48.7-49.9) between 2005 and 2016 in Ethiopia. The prevalence was 47.6% (95%CI: 46.1-49.1) in 2005, 42.8% (95%CI: 41.8-43.8) in 2011, and increased to 57.4% (95%CI: 56.3-58.4) in 2016. The pooled data showed that children from households practising open defecation were more likely to be anaemic (AOR: 1.19, 95% CI: 1.05-1.36). In our survey specify analysis, the odds of anaemia were higher among children from households practising open defecation (AOR: 1.33, 95% CI: 1.12-1.58) in the EDHS-2011 and EDHS-2016 (AOR: 1.49, 95% CI: 1.13-1.90). In contrast, neither household water sources nor the time to obtain water was associated with anaemia after controlling for potential confounders. The other variables significantly associated with childhood anaemia include: the child's age (6-35 months), not fully vaccinated (AOR: 1.14, 95%CI: 1.05-1.24), children not dewormed in the last 6 months (AOR: 1.11, 95%CI: 1.01-1.24), children born to mothers not working (AOR: 1.10, 95%CI: 1.02-1.19), children from poor households (AOR: 1.18: 95%CI: 1.06-1.31), and rural residence (AOR: 1.23, 95%CI: 1.06-1.42). CONCLUSION: In Ethiopia, about fifty percent of children suffer from childhood anemia, making it a serious public health issue. Open defecation is a major contributing factor to this scourge. To address this issue effectively, it is recommended to strengthen initiatives aimed at eliminating open defecation that involve various approaches, including sanitation infrastructure development, behavior change campaigns, and policy interventions. In addition, to reduce the burden of anemia in children, a multi-faceted approach is necessary, involving both prevention and treatment strategies.

Mapping and predicting open defecation in Ethiopia: 2021 PMA-ET study.

INTRODUCTION: There has been extensive research conducted on open defecation in Ethiopia, but a notable gap persists in comprehensively understanding the spatial variation and predictors at the household level. This study utilizes data from the 2021 Performance Monitoring for Action Ethiopia (PMA-ET) to address this gap by identifying hotspots and predictors of open defecation. Employing geographically weighted regression analysis, it goes beyond traditional models to account for spatial heterogeneity, offering a nuanced understanding of geographical variations in open defecation prevalence and its determinants. This research pinpoints hotspot areas and significant predictors, aiding policymakers and practitioners in tailoring interventions effectively. It not only fills the knowledge gap in Ethiopia but also informs global sanitation initiatives. METHODS: The study comprised a total weighted sample of 24,747 household participants. ArcGIS version 10.7 and SaT Scan version 9.6 were used to handle mapping, hotspots, ordinary least squares, Bernoulli model analysis, and Spatial regression. Bernoulli-based model was used to analyze the purely spatial cluster detection of open defecation at the household level in Ethiopia. Ordinary Least Square (OLS) analysis and geographically weighted regression analysis were employed to assess the association between an open defecation and explanatory variables. RESULTS: The spatial distribution of open defecation at the household level exhibited clustering (global Moran's I index value of 4.540385, coupled with a p-value of less than 0.001), with significant hotspots identified in Amhara, Afar, Harari, and parts of Dire Dawa. Spatial analysis using Kuldorff's Scan identified six clusters, with four showing statistical significance (P-value < 0.05) in Amhara, Afar, Harari, Tigray, and southwest Ethiopia. In the geographically weighted regression model, being male [coefficient = 0.87, P-value < 0.05] and having no media exposure (not watching TV or listening to the radio) [coefficient = 0.47, P-value < 0.05] emerged as statistically significant predictors of household-level open defecation in Ethiopia. CONCLUSION: The study revealed that open defecation at the household level in Ethiopia varies across the regions, with significant hotspots identified in Amhara, Afar, Harari, and parts of Dire Dawa. Geographically weighted regression analysis highlights male participants lacking media exposure as substantial predictors of open defecation. Targeted interventions in Ethiopia should improve media exposure among males in hotspot regions, tailored sanitation programs, and region-specific awareness campaigns. Collaboration with local communities is crucial.

Childhood undernutrition mediates the relationship between open defecation with anemia among Ethiopian children: a nationally representative cross-sectional study.

BACKGROUND: Poor sanitation and/or open defecation are a significant public health problem in Ethiopia, where access to improved sanitation facilities is still limited. There is a growing body of literature about the effect of open defecation on children's linear growth failure. However, very few studies about the effects of open defecation on child anemia exist. In this study, we examine whether childhood undernutrition (i.e. stunting, wasting, and underweight) mediates the relationship between open defecation and childhood anemia in children aged 6-59 months in Ethiopia. METHODS: We used pooled Ethiopia Demographic and Health Survey data (2005-2016) comprising 21,918 (weighted data) children aged 6-59 months. Anemia was defined as an altitude-adjusted hemoglobin (Hb) level of less than 11 g/deciliter (g/dl) for children under 5 years. Childhood undernutrition was assessed using height-for-age Z-scores (HAZ), weight-for-age Z-scores (WAZ), and weight-for-height Z-scores (WHZ) for stunting, wasting, and underweight respectively. Mediation effects were calculated using the bootstrap and the indirect effect was considered significant when the 95% bootstrap confidence intervals (95% CI) did not contain zero. Moreover, separate multilevel regression analyses were used to explore the statistical association between open defecation and child anemia, after adjusting for potential confounders. RESULTS: Our analysis revealed that nearly half (49.6%) of children aged 6 to 59 months were anemic, 46.8% were stunted, 9.9% were wasted, and 29.5% were underweight. Additionally, 45.1% of children belonged to households that practiced open defecation (OD). Open defecation was associated with anemia (AOR: 1.28; 95% CI: 1.18-1.39) and it positively predicted anemia with direct effect of ß = 0.233, p < 0.001. Childhood undernutrition showed a partial mediating role in the relationship between OD and anemia. Analyzing the indirect effects, results revealed that child undernutrition significantly mediated the relationship between open defecation and anemia (stunting (ßindirect = 0.014, p < 0.001), wasting (ßindirect = 0.009, p = 0.002), and underweight (ßindirect = 0.012, p < 0.001)). When the mediating role of child undernutrition was accounted for, open defecation had a positive impact on anemia with a total effect of ßtotal = 0.285, p < 0.001. CONCLUSION: Open defecation showed a significant direct effect on anemia. Child undernutrition remarkably mediated the relationship between OD and anemia that further magnified the effect. This finding has an important programmatic implication calling for strengthened, accelerated and large-scale implementation of strategies to end open defecation and achieve universal access to sanitation in Ethiopia.

Early safety and efficiency outcomes of a novel interdisciplinary laparoscopic resection rectopexy combined with sacrocolpopexy for women with obstructive defecation syndrome and pelvic organ prolapse: a single center study.

BACKGROUND: Obstructive defecation syndrome (ODS) defines a disturbed defecation process frequently associated with pelvic organ prolapse (POP) in women that substantially compromises quality of life. Conservative management offers limited relief and a surgical intervention may be required. This is characterized by individual approaches. AIM OF THE STUDY: This retrospective single center study evaluated the surgical and clinical short-term outcome of a novel interdisciplinary laparoscopic resection rectopexy (L-RRP) with mesh- sacrocolpopexy (L-SCP) for women suffering from ODS and POP. METHODS: The study participants underwent surgery in an interdisciplinary laparoscopic approach. Safety was the primary endpoint, assessed via postoperative morbidity classified by Clavien-Dindo scale. Secondary outcomes included evaluation of bowel function, fecal and urinary incontinence and pelvic organ prolapse status at 12 months follow-up. Additionally, a biological mesh (BM) was offered to women, who asked for an alternative to synthetic mesh material (SM). RESULTS: Of the 44 consecutive patients requiring surgery for ODS and POP, 36 patients underwent the interdisciplinary surgical approach; 28 patients with SM and 8 patients with BM. In total 5 complications occurred, four of them were classified as minor. One minor complication was observed in the BM group. One anastomotic leakage occurred in the SM group. The two ODS scores, the bowel dysfunction score, and the incontinence score improved significantly (p = 0.006, p = 0.003, p < 0.001, and p = 0.0035, respectively). Pelvic floor anatomy was fully restored (POP-Q 0) for 29 (80%) patients after surgery. 17 patients (47%) suffered from urinary incontinence before surgery, which was restored in 13 patients (76.5%). CONCLUSIONS: The interdisciplinary approach with L-RRP and L-SCP and the use of a BM in a small subgroup were technically feasible, safe, and effective in this single center setting. The study's retrospective design, the small sample size and the lack of comparators limit the generalizability of the findings requiring future randomized trials. TRIAL REGISTRATION: Retrospectively registered at clinicaltrials.gov, trial number NCT05910021, date of registration 06/10/2023.

Machine learning-based prediction models affecting the recovery of postoperative bowel function for patients undergoing colorectal surgeries.

PURPOSE: The debate surrounding factors influencing postoperative flatus and defecation in patients undergoing colorectal resection prompted this study. Our objective was to identify independent risk factors and develop prediction models for postoperative bowel function in patients undergoing colorectal surgeries. METHODS: A retrospective analysis of medical records was conducted for patients who undergoing colorectal surgeries at Peking University People's Hospital from January 2015 to October 2021. Machine learning algorithms were employed to identify risk factors and construct prediction models for the time of the first postoperative flatus and defecation. The prediction models were evaluated using sensitivity, specificity, the Youden index, and the area under the receiver operating characteristic curve (AUC) through logistic regression, random forest, Naïve Bayes, and extreme gradient boosting algorithms. RESULTS: The study included 1358 patients for postoperative flatus timing analysis and 1430 patients for postoperative defecation timing analysis between January 2015 and December 2020 as part of the training phase. Additionally, a validation set comprised 200 patients who undergoing colorectal surgeries from January to October 2021. The logistic regression prediction model exhibited the highest AUC (0.78) for predicting the timing of the first postoperative flatus. Identified independent risk factors influencing the time of first postoperative flatus were Age (p < 0.01), oral laxatives for bowel preparation (p = 0.01), probiotics (p = 0.02), oral antibiotics for bowel preparation (p = 0.02), duration of operation (p = 0.02), postoperative fortified antibiotics (p = 0.02), and time of first postoperative feeding (p < 0.01). Furthermore, logistic regression achieved an AUC of 0.72 for predicting the time of first postoperative defecation, with age (p < 0.01), oral antibiotics for bowel preparation (p = 0.01), probiotics (p = 0.01), and time of first postoperative feeding (p < 0.01) identified as independent risk factors. CONCLUSIONS: The study suggests that he use of probiotics and early recovery of diet may enhance the recovery of bowel function in patients undergoing colorectal surgeries. Among the various analytical methods used, logistic regression emerged as the most effective approach for predicting the timing of the first postoperative flatus and defecation in this patient population.

Analysis of factors that indicated surgery in 400 patients submitted to a complete diagnostic workup for obstructed defecation syndrome and rectal prolapse using a supervised machine learning algorithm.

BACKGROUND: Patient selection is extremely important in obstructed defecation syndrome (ODS) and rectal prolapse (RP) surgery. This study assessed factors that guided the indications for ODS and RP surgery and their specific role in our decision-making process using a machine learning approach. METHODS: This is a retrospective analysis of a long-term prospective observational study on female patients reporting symptoms of ODS who underwent a complete diagnostic workup from January 2010 to December 2021 at an academic tertiary referral center. Clinical, defecographic, and other functional tests data were assessed. A supervised machine learning algorithm using a classification tree model was performed and tested. RESULTS: A total of 400 patients were included. The factors associated with a significantly higher probability of undergoing surgery were follows: as symptoms, perineal splinting, anal or vaginal self-digitations, sensation of external RP, episodes of fecal incontinence and soiling; as physical examination features, evidence of internal and external RP, rectocele, enterocele, or anterior/middle pelvic organs prolapse; as defecographic findings, intra-anal and external RP, rectocele, incomplete rectocele emptying, enterocele, cystocele, and colpo-hysterocele. Surgery was less indicated in patients with dyssynergia, severe anxiety and depression. All these factors were included in a supervised machine learning algorithm. The model showed high accuracy on the test dataset (79%, p < 0.001). CONCLUSIONS: Symptoms assessment and physical examination proved to be fundamental, but other functional tests should also be considered. By adopting a machine learning model in further ODS and RP centers, indications for surgery could be more easily and reliably identified and shared.

Deciphering the Impact of Defecation Frequency on Gut Microbiome Composition and Diversity.

This study explores the impact of defecation frequency on the gut microbiome structure by analyzing fecal samples from individuals categorized by defecation frequency: infrequent (1-3 times/week, n = 4), mid-frequent (4-6 times/week, n = 7), and frequent (daily, n = 9). Utilizing 16S rRNA gene-based sequencing and LC-MS/MS metabolome profiling, significant differences in microbial diversity and community structures among the groups were observed. The infrequent group showed higher microbial diversity, with community structures significantly varying with defecation frequency, a pattern consistent across all sampling time points. The Ruminococcus genus was predominant in the infrequent group, but decreased with more frequent defecation, while the Bacteroides genus was more common in the frequent group, decreasing as defecation frequency lessened. The infrequent group demonstrated enriched biosynthesis genes for aromatic amino acids and branched-chain amino acids (BCAAs), in contrast to the frequent group, which had a higher prevalence of genes for BCAA catabolism. Metabolome analysis revealed higher levels of metabolites derived from aromatic amino acids and BCAA metabolism in the infrequent group, and lower levels of BCAA-derived metabolites in the frequent group, consistent with their predicted metagenomic functions. These findings underscore the importance of considering stool consistency/frequency in understanding the factors influencing the gut microbiome.

Characterization of obstructive defecation from a structural and a functional perspective.

BACKGROUND/AIMS: Defecation disorders can occur as a consequence of functional or structural anorectal dysfunctions during voiding. The aims of this study is to assess the prevalence of structural (SDD) vs functional (FDD) defecation disorders among patients with clinical complaints of obstructive defecation (OD) and their relationship with patients' expulsive capacity. PATIENTS AND METHODS: Retrospective study of 588 patients with OD studied between 2012 and 2020 with evacuation defecography (ED), and anorectal manometry (ARM) in a subgroup of 294. RESULTS: 90.3% patients were women, age was 58.5±12.4 years. Most (83.7%) had SDD (43.7% rectocele, 45.3% prolapse, 19.3% enterocele, and 8.5% megarectum), all SDD being more prevalent in women except for megarectum. Functional assessments showed: (a) absence of rectification of anorectal angle in 51% of patients and poor pelvic descent in 31.6% at ED and (b) dyssynergic defecation in 89.9%, hypertonic IAS in 44%, and 33.3% rectal hyposensitivity, at ARM. Overall, 46.4% of patients were categorized as pure SDD, 37.3% a combination of SDD+FDD, and 16.3% as having pure FDD. Rectal emptying was impaired in 66.2% of SDD, 71.3% of FDD and in 78% of patients with both (p=0.017). CONCLUSIONS: There was a high prevalence of SDD in middle-aged women with complaints of OD. Incomplete rectal emptying was more prevalent in FDD than in SDD although FDD and SDD frequently coexist. We recommend a stepwise therapeutic approach always starting with therapy directed to improve FDD and relaxation of striated pelvic floor muscles.

Essential roles of the hypothalamic A11 region and the medullary raphe nuclei in regulation of colorectal motility in rats.

The supraspinal brain regions controlling defecation reflex remain to be elucidated. The purpose of this study was to determine the roles of the hypothalamic A11 region and the medullary raphe nuclei in regulation of defecation. For chemogenetic manipulation of specific neurons, we used the double virus vector infection method in rats. hM3Dq or hM4Di was expressed in neurons of the A11 region and/or the raphe nuclei that send output to the lumbosacral defecation center. Immunohistological and functional experiments revealed that both the A11 region and the raphe nuclei directly connected with the lumbosacral spinal cord through descending pathways composed of stimulatory monoaminergic neurons. Stimulation of the hM3Dq-expressing neurons in the A11 region or the raphe nuclei enhanced colorectal motility only when GABAergic transmission in the lumbosacral spinal cord was blocked by bicuculline. Experiments using inhibitory hM4Di-expressing rats revealed that enhancement of colorectal motility caused by noxious stimuli in the colon is mediated by both the A11 region and the raphe nuclei. Furthermore, suppression of the A11 region and/or the raphe nuclei significantly inhibited water avoidance stress-induced defecation. These findings demonstrate that the A11 region and the raphe nuclei play an essential role in the regulation of colorectal motility. This is important because brain regions that mediate both intracolonic noxious stimuli-induced defecation and stress-induced defecation have been clarified for the first time.NEW & NOTEWORTHY The A11 region and the raphe nuclei, constituting descending pain inhibitory pathways, are related to both intracolonic noxious stimuli-induced colorectal motility and stress-induced defecation. Our findings may provide an explanation for the concurrent appearance of abdominal pain and defecation disorders in patients with irritable bowel syndrome. Furthermore, overlap of the pathway controlling colorectal motility with the pathway mediating stress responses may explain why stress exacerbates bowel symptoms.

Comparison of Anorectal Manometry, Rectal Balloon Expulsion Test, and Defecography for Diagnosing Defecatory Disorders.

BACKGROUND & AIMS: The utility of high-resolution anorectal manometry (HR-ARM) for diagnosing defecatory disorders (DDs) is unclear because healthy people may have features of dyssynergia. We aimed to identify objective diagnostic criteria for DD and to ascertain the utility of HR-ARM for diagnosing DD. METHODS: Constipated patients were assessed with HR-ARM and rectal balloon expulsion time (BET), and a subset underwent defecography. Normal values were established by assessing 184 sex-matched healthy individuals. Logistic regression models evaluated the association of abnormal HR-ARM findings with prolonged BET and reduced rectal evacuation (determined by defecography). RESULTS: A total of 474 constipated individuals (420 women) underwent HR-ARM and BET, and 158 underwent defecography. BET was prolonged, suggesting a DD, for 152 patients (32%). Rectal evacuation was lower for patients with prolonged vs normal BET. A lower rectoanal gradient during evacuation, reduced anal squeeze increment, and reduced rectal sensation were independently associated with abnormal BETs; the rectoanal gradient was 36% sensitive and 85% specific for prolonged BET. A lower rectoanal gradient and prolonged BET were independently associated with reduced evacuation. Among constipated patients, the probability of reduced rectal evacuation was 14% when the gradient and BET were both normal, 45% when either was abnormal, and 75% when both variables were abnormal. CONCLUSIONS: HR-ARM, BET, and defecography findings were concordant for constipated patients, and reduced rectoanal gradient was the best HR-ARM predictor of prolonged BET or reduced rectal evacuation. Prolonged BET, reduced gradient, and reduced evacuation each independently supported a diagnosis of DD in constipated patients. We propose the terms probable DD for patients with an isolated abnormal gradient or BET and definite DD for patients with abnormal results from both tests.

Optimizing the Utility of Anorectal Manometry for Diagnosis and Therapy: A Roundtable Review and Recommendations.

BACKGROUND & AIMS: Anorectal manometry (ARM) is a comprehensive diagnostic tool for evaluating patients with constipation, fecal incontinence, or anorectal pain; however, it is not widely utilized for reasons that remain unclear. The aim of this roundtable discussion was to critically examine the current clinical practices of ARM and biofeedback therapy by physicians and surgeons in both academic and community settings. METHODS: Leaders in medical and surgical gastroenterology and physical therapy with interest in anorectal disorders were surveyed regarding practice patterns and utilization of these technologies. Subsequently, a roundtable was held to discuss survey results, explore current diagnostic and therapeutic challenges with these technologies, review the literature, and generate consensus-based recommendations. RESULTS: ARM identifies key pathophysiological abnormalities such as dyssynergic defecation, anal sphincter weakness, or rectal sensory dysfunction, and is a critical component of biofeedback therapy, an evidence-based treatment for patients with dyssynergic defecation and fecal incontinence. Additionally, ARM has the potential to enhance health-related quality of life and reduce healthcare costs. However, it has significant barriers that include a lack of education and training of healthcare providers regarding the utility and availability of ARM and biofeedback procedures, as well as challenges with condition-specific testing protocols and interpretation. Additional barriers include understanding when to perform, where to refer, and how to use these technologies, and confusion over billing practices. CONCLUSIONS: Overcoming these challenges with appropriate education, training, collaborative research, and evidence-based guidelines for ARM testing and biofeedback therapy could significantly enhance patient care of anorectal disorders.

An Office-Based, Point-of-Care Test Predicts Treatment Outcomes With Community-Based Pelvic Floor Physical Therapy in Patients With Chronic Constipation.

BACKGROUND & AIMS: Rectal evacuation disorders are common among constipated patients. We aimed to evaluate the accuracy of an investigational point-of-care test (rectal expulsion device [RED]) to predict outcomes with community-based pelvic floor physical therapy. METHODS: We enrolled patients meeting Rome IV criteria for functional constipation failing fiber/laxatives for more than 2 weeks. RED was inserted and self-inflated, and then time-to-expel was measured in a left lateral position. All patients underwent empiric community-based pelvic floor physical therapy in routine care with outcomes measured at 12 weeks. The primary end point was global clinical response (Patient Assessment of Constipation Symptoms score reduction, >0.75 vs baseline). Secondary end points included improvement in health-related quality-of-life (Patient Assessment of Constipation Quality of Life score reduction, >1.0) and complete spontaneous bowel movement frequency (Food and Drug Administration complete spontaneous bowel movement responder definition). RESULTS: Thirty-nine patients enrolled in a feasibility phase to develop the use-case protocol. Sixty patients enrolled in a blinded validation phase; 52 patients (mean, 46.9 y; 94.2% women) were included in the intention-to-treat analysis. In the left lateral position, RED predicted global clinical response (generalized area under the curve [gAUC], 0.67; 95% CI, 0.58-0.76]), health-related quality-of-life response (gAUC, 0.67; 95% CI, 0.58-0.77; P < .001), and complete spontaneous bowel movement response (gAUC, 0.63; 95% CI, 0.57-0.71; P < .001). As a screening test, a normal RED effectively rules out evacuation disorders (expected clinical response, 8.9%; P = .042). Abnormal RED in the left lateral position (defined as expulsion within 5 seconds or >120 seconds) predicted 48.9% clinical response to physical therapy. A seated maneuver enhanced the likelihood of clinical response (71.1% response with seated RED retained >13 seconds) but likely is unnecessary in most settings. CONCLUSIONS: RED offers an opportunity to disrupt the paradigm by offering a personalized approach to managing chronic constipation in the community (Clinicaltrials.gov: NCT04159350).